We propose to develop and demonstrate a novel microfluidic device and assay for selection and optimization of delivery vehicles, specifically non-viral vectors for drug delivery to tumors. Tumor drug delivery is a complex phenomenon affected by several elements in addition to drug or delivery vehicle's physico-chemical properties. A key factor is tumor microvasculature with complex effects including convective transport, high interstitial pressure and enhanced vascular permeability due to the presence of leaky vessels. Current in vitro models of tumor drug delivery are oversimplified and, as a result, show poor correlation with in vivo performance. We propose to develop a novel microfluidic platform that models the tumor microenvironment more accurately, with physiologically and morphologically realistic microvasculature including endothelial cell lined leaky capillary vessels along with 3D solid tumors. This device will allow real-time, quantitative assessment of the performance of delivery vehicles under in vivo like conditions. In Phase I, we designed and fabricated prototypes of plastic microfluidic chips with embedded microvascular networks with leaky gaps. Endothelial cells and 3D spheroids of cervical tumor cells were co-cultured in the networks. Drug vehicle screening was successfully demonstrated using gene delivery nanopolymers. Planned Phase II enhancements include optimization of leaky vasculature in addition to extension of the device for culture of breast, ovary and lung tumor cells. The ability of the microfluidic device for screening of drug delivery vehicle screening for targeted drug delivery and the role of particle shape for delivery in addition to gene delivery wil be investigated. A multi-disciplinary (engineering and biology), industry-academic team with substantial expertise has been assembled for successful execution of this challenging project. The developed device will have critical applications both in basic research, where it can be used to develop next generation delivery vehicles, and in drug discovery where it can be used to study drug efficacy in realistic tumor microenvironment. The product will be commercialized to pharmaceutical/biotech firms, drug research labs and universities/non-profit centers engaged in cancer research and drug delivery. PUBLIC HEALTH RELEVANCE: The developed device will have critical applications both in basic research, where it can be used to characterize and develop next generation delivery vehicles, and in drug discovery where it can be used to study the efficacy of the drug in these realistic tumor microvascular networks. The product will be commercialized to pharmaceutical/biotech firms, drug research labs and universities/non-profit centers engaged in cancer research and drug delivery.